KR20070103493A - Use of 2-anilino-3,4-dihydro-quinazolin as a 5HT5A receptor antagonist - Google Patents

Abstract

The present invention relates to the use of a compound of formula (I) and a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of 5-HT _5A receptor related diseases:

Formula I

Where

R ¹ is hydrogen, lower alkyl or halogen;

R ² is hydrogen, lower alkyl, lower alkoxy, halogen, lower alkyl substituted by halogen or cyano;

Aryl is phenyl, naphthyl or indan-5-yl;

n is 1 or 2.

Description

USE OF 2-ANILINO-3,4-DIHYDRO-QUINAZOLINES AS 5HT5A RECEPTOR ANTAGONISTS as a 5HT5A receptor antagonist

The present invention relates to the use of a compound of formula (I) and a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of 5-HT _5A receptor related diseases:

Where

R ¹ is hydrogen, lower alkyl or halogen;

R ² is hydrogen, lower alkyl, lower alkoxy, halogen, lower alkyl substituted by halogen or cyano;

Aryl is phenyl, naphthyl or indan-5-yl;

n is 1 or 2.

The compounds disclosed by the formula (I) are partly known. Related compounds described in US Pat. No. 3,517,005 and US Pat. No. 3,496,179 have bronchial dilatation and / or hypotension activity.

It has been found that the compound of formula I has good activity on the 5-HT _5A receptor. Therefore, the present invention is directed to depression (bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without mental characteristics, tonic features, depressive aspects, atypical features or postpartum development, seasonal affective disorders and dysthymic disorders, and Depressive disorders caused by general medical conditions, including but not limited to myocardial infarction, diabetes, abortion or miscarriage; anxiety disorders (general anxiety disorders and social anxiety disorders), schizophrenia, panic disorder, agoraphobia, social Phobias, obsessive compulsive disorder, post-traumatic stress disorder, pain (especially neuropathic pain), memory disorders (including dementia, forgetfulness and age-related memory impairment), eating behavior disorders (including neuronal anorexia and anorexia nervosa), sexual dysfunction, Sleep disorders (including cross-sleep disorders, abnormal sleep, insomnia, sleep apnea and narcolepsy), withdrawal due to substance abuse (eg, cocaine, ethanol, nicotine , Benzodiazepines, alcohols, caffeine, phencycline and phencycline-like compounds, opiates such as canavi, heroin, morphine, soothing hypnotics, amphetamines or amphetamines), motility disorders such as Parkinson's disease, Parkinson's The use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of dementia in the disease, neuroleptic-induced Parkinsonism, tardive dyskinesia, and other mental and gastrointestinal disorders such as irritable bowel syndrome (WO 2004/096771).

The neurotransmitter 5-hydroxytryptamine (5-HT, serotonin) regulates a wide range of physiological and pathological processes of the central and peripheral nervous system, including anxiety, sleep control, aggressiveness, lactation and depression (see [ Hoyer et al., Pharmacol. Rev. 46, 157-204, 1994]. Pharmacological characterization and molecular replication of several 5-HT receptor genes have revealed that 5-HT mediates its various physiological activities through diversity of receptor subtypes. These receptors belong to two or more different protein superfamily: ligand-gated ion channel receptor (5-HT ₃ ) and G-protein binding 7-transmembrane receptor (13 distinct receptors recently replicated). In addition, serotonin in G-protein coupled receptors is active through a variety of signal transduction mechanisms.

Replication and characterization of human 5-HT _5A serotonin receptors is described in FEBS Letters, 355, 242-246 (1994). The sequence is not closely related to the sequence of any previously known serotonin receptor with up to 35% similarity to the human 5-HT _1B receptor. It encodes a predetermined 357 amino acid protein with a presumed seven transmembrane domain, consistent with the G-protein binding receptor. This sequence is characterized by containing an intron between the transmembrane domains V and VI. More recently binding to Gi / o α mechanisms has been demonstrated with inhibition of forskolin-stimulated cAMP and also evidence for more complex G-protein mediated binding mechanisms (Francken et al., Eur J. Pharmacol. 361, 299-309, 1998; Noda et al., J. Neurochem. 84, 222-232, 2003).

WO 2004/096771 also describes depression, anxiety disorder, schizophrenia, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder, post traumatic stress disorder, pain, memory disorder, dementia, eating behavior disorder, sexual dysfunction, sleep disorder, It describes the use of active compounds on the 5-HT _5A serotonin receptor for the treatment of withdrawal, drug disorders such as Parkinson's disease, mental disorders or gastrointestinal disorders due to drug abuse. The Journal of Psychiatric Research, 38, 371-376 (2004) describes evidence for the potential important role of the 5-HT _5A gene in patients with schizophrenia, and more particularly later onset.

Preferred symptoms related to the present invention include anxiety, depression, sleep disorders and schizophrenia.

As used herein, the term "lower alkyl" refers to a saturated straight or branched chain alkyl group having 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t -Butyl etc. are shown. Preferred alkyl groups are groups of 1 to 4 carbon atoms.

The term "lower alkoxy" refers to a group in which an alkyl moiety is as defined above and bonded via an oxygen atom.

The term "halogen" refers to chlorine, iodine, fluorine and bromine.

The term "aryl" refers to a monovalent cyclic aromatic hydrocarbon radical composed of one or more fused rings in which one or more rings are substantially aromatic, examples being phenyl, naphthyl or indan-5-yl.

The term "pharmaceutically acceptable acid addition salts" refers to inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p- Salts with toluenesulfonic acid and the like.

Preferred compounds of formula (I) are those in which the aryl group is phenyl, for example:

(5-methyl-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine,

(3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine,

(5-chloro-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine,

(3,4-dihydro-quinazolin-2-yl) -m-tolyl-amine,

(3-bromo-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine,

(5,6-dichloro-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine,

(4-chloro-3-trifluoromethyl-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine,

(3-chloro-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine,

(3,5-bis-trifluoromethyl-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine,

(3,4-dihydro-quinazolin-2-yl)-(3-methoxy-phenyl) -amine, or

(3,4-Dihydro-quinazolin-2-yl)-(3-fluoro-phenyl) -amine.

Further preferred compounds are compounds wherein the aryl group is indan-5-yl, for example (3,4-dihydro-quinazolin-2-yl) -indan-5-yl-amine.

Further preferred compounds are compounds wherein the aryl group is naphthyl, for example (3,4-dihydro-quinazolin-2-yl) -naphthalen-1-yl-amine.

The present compounds of formula (I) and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example the methods described below:

a) reacting a compound of formula II with MeI to obtain a compound of formula I; or

b) reacting a compound of formula III with a compound of formula IV to yield a compound of formula I; And

c) if necessary, converting the obtained compound into a pharmaceutically acceptable acid addition salt:

Formula I

Where

R ¹ , R ² , aryl and n are as defined above.

The preparation of the compounds of formula (I) in Examples 1 to 23 and Schemes 1 and 2 below are described in more detail. Starting materials are known compounds or compounds which can be prepared according to methods known in the art.

To a solution of 2-aminobenzylamine of formula V in a solvent such as ethyl acetate, arylisothiocyanate of formula VI is added and the mixture is heated for about 12 hours. After cooling, the reaction mixture is concentrated, dried and purified by conventional methods. To a solution of thiourea of formula (II) obtained above in a solvent such as ethanol, an alkylating agent such as methyliodide is added and the mixture is heated to reflux for about 3 hours. From the reaction mixture, (3,4-dihydro-quinazolin-2-yl) -aryl-amine of formula (I) is obtained by conventional purification methods.

Aryldithiocarbamic acid methyl esters of formula (VIII) are described in J. Pat. Garin, V. Martinez, J. Mayoral, E. Melendez, F. Merchan: Synthesis 1981, 961.

Aryldithiocarbonimidates of formula III are described in J. Pat. Garin, E. Melendez, F. L. Merchan, C. Tejel, and T. Tejero: Synthesis 1983, 375-376.

Carbon disulfide and a base such as sodium hydroxide are added to a solution of the arylamine of formula VII in a suitable solvent such as DMSO. After about 30 minutes, methyl iodide is added and the mixture is reacted for about 12 hours. The reaction mixture is then worked up and the aryldithiocarbamic acid methyl ester of formula VIII obtained is purified in a conventional manner. Bases such as sodium hydroxide and methyl iodide are then added to a solution of the aryldithiocarbamic acid methyl ester of formula VIII obtained above in a solvent such as DMF and the mixture is allowed to react for about 1.5 hours. The reaction mixture is then worked up and purified by conventional methods to afford aryldithiocarbonidate of formula III. The compound of formula III is heated in a solvent such as DMSO with 2-benzylamine of formula IV and a suitable base such as sodium hydroxide for about 3 hours. Conventional workup and purification from the reaction mixture affords (3,4-dihydro-quinazolin-2-yl) -aryl-amine of formula (I).

As mentioned above, the compounds of formula (I) and their pharmaceutically usable addition salts have valuable pharmaceutical properties. The compounds of the present invention have activity on the 5-HT _5A receptors such as depression, anxiety disorder, schizophrenia, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder, post traumatic stress disorder, pain, memory disorder, dementia, eating behavior disorder, It has been found to be suitable for the treatment of sexual dysfunction, sleep disorders, withdrawal due to drug abuse, motility disorders such as Parkinson's disease, mental disorders or gastrointestinal disorders.

Test technology

[ ³ H] LSD radioligand binding assay showed the affinity of the compound for recombinant human 5-HT _5A receptor on the membrane from 5-HT _5A receptor transiently (cDNA) expressed in human embryonic kidney-EBNA (HEK-EBNA) cells. Was used to determine. Assay buffer consisted of Tris (50 mM) buffer containing 1 mM EGTA, 10 mM MgCl ₂ (pH 7.4) and 10 μM pargiline. Binding assays were performed on 96 well plates in the presence of [ ³ H] LSD (about 1 nM), about 2 μM per membrane protein well, and 0.5 mg of Ysi-poly-1-lysine SPA beads in 200 μl final volume of buffer. It became. Nonspecific binding was found using 2 μM of methiotepine. Compounds were tested at 10 concentrations. All analyzes were performed in duplicate and repeated two more times. Assay plates were incubated for 120 minutes at room temperature before centrifugation. Binding ligands were measured using a Packard Topcount scintillation counter. IC ₅₀ values were calculated using a nonlinear curve fitting program, and Ki values were calculated using the Cheng-Prussoff equation.

The activity of the compounds is shown in the table below:

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, for example in the form of suppositories, orally, for example in the form of injections.

The compounds of formula (I) can be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. However, depending on the nature of the active substance, no carrier is usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The formulations may also contain other therapeutically valuable substances.

Agents containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier may also contain one or more compounds of formula (I) and / or pharmaceutically acceptable acid addition salts, and optionally one or more It is an object of the present invention as well as methods for its preparation, which comprise other therapeutically valuable substances into herbal dosage forms with one or more therapeutically inert carriers.

Most preferred symptoms according to the invention include disorders of the central nervous system such as anxiety, depression, sleep disorders and schizophrenia.

Dosages may vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. For oral administration, the adult dosage of the compound of formula I or a corresponding amount of the pharmaceutically acceptable salt may be about 0.01 mg to about 1000 mg per day. The daily dose may be administered as a single dose or as a divided dose, furthermore the upper limit may also be exceeded when instructed.

Manufacturing process

1. Mix items 1, 2, 3 and 4 and granulate using purified water.

2. Dry the granules at 50 ° C.

3. Pass the granules through a suitable grinding device.

4. Add item 5 and mix for 3 minutes; Compress on a suitable press.

Manufacturing process

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

Compounds of formula I can be prepared as shown in the following description:

Example 1

(5-Methyl-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine

a) 1- (2-amino-6-methyl-benzyl) -3- (3-trifluoromethyl-phenyl) -thiourea

3- (trifluoromethyl) phenyl isothiocyanate (224 mg, 1.10 mmol) was added to a solution of 2-aminomethyl-3-methyl-phenylamine (150 mg, 1.10 mmol) in ethyl acetate (3 ml) and The reaction mixture was shaken overnight at 80 ° C. in a screw-cap vial. For post treatment, more ethyl acetate was added and the mixture was washed with water and brine and dried (Na ₂ SO ₄ ). After evaporation of the solvent under reduced pressure, the residue was purified (silica gel, heptane / ethyl acetate = 100: 0-80:20) to give the title compound (50 mg, 13%).

b) (5-methyl-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine

Methyl iodide (167 mg, 1.18 mmol) and 1- (2-amino-6-methyl-benzyl) -3- (3-trifluoromethyl-phenyl) -thiourea (50 mg) in ethanol (3 ml) , 0.147 mmol) was heated to reflux for 3 hours. The solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate, washed (water) and dried (Na ₂ SO ₄ ). After evaporation of the solvent under reduced pressure, the residue was purified by HPLC (YMC CombiPrep C18 column 50 × 20 mm, solvent gradient in 0.1% TFA (aq) over 6.0 min 5-95% CH ₃ CN, λ = 230 nm, flow rate 40 ml / min) The title compound was obtained (4 mg, 8.9%, MS: m / e = 306.1 [M + H ⁺ ]).

Example 2

(3,4-Dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine

a) (3-trifluoromethyl-phenyl) -dithiocarbamic acid methyl ester

Under a nitrogen atmosphere, carbon disulfide (0.73 ml, 12 mmol) was added to a solution of 3-aminobenzotrifluoride (1.50 g, 9.3 mmol) in DMSO (10 ml). Subsequently, sodium hydroxide (0.56 ml, aqueous solution, 20 mol / l, 11 mmol) was added and the dark brown reaction mixture was stirred for 30 minutes (room temperature). The mixture turned yellow with the addition of methyl iodide (730 ml, 12 mmol), which was stirred overnight (room temperature). The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried (Na ₂ SO ₄ ) and the solvent was evaporated under reduced pressure. The residue was purified (silica gel, heptane / ethyl acetate = 100: 0-80:20) to give the title compound (1.65 g, 71%).

b) (3-Trifluoromethyl-phenyl) -dimethyl-dithiocarbonidate

Under nitrogen atmosphere, sodium hydroxide (0.39 ml, aqueous solution, 20 mol / l, 8 mmol) was added (3-trifluoromethyl-phenyl) -dithiocarbamic acid methyl ester (1.65 g, 6.57 mmol) in DMF (10 ml). ) Was added to the solution. Then methyl iodide (0.53 ml, 8.52 mmol) was added and the mixture was stirred for 1.5 hours (room temperature). The mixture was taken up in ethyl acetate, washed (water) and dried (Na ₂ SO ₄ ). As the solvent evaporated under reduced pressure, the residue was purified (silica gel, heptane / ethyl acetate = 100: 0-90:10) to give the title compound (1.50 g, 86%).

c) (3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine

Under a nitrogen atmosphere, sodium hydroxide (0.1 ml, aqueous solution, 20 mol / l, 2 mmol) was added to a solution of 2-aminobenzylamine (92 mg, 0.75 mmol) in DMSO (1 ml). After 30 minutes, a solution of (3-trifluoromethyl-phenyl) -dimethyl-dithiocarbonimidate (200 mg, 0.75 mmol) in DMSO (1 ml) was added and the mixture was heated to 190 ° C. for 3 hours. . The title compound from the reaction mixture by preparative reverse phase HPLC (YMC Combiprep C18 column 50 × 20 mm, solvent gradient 5-95% CH ₃ CN, λ = 230 nm, flow rate 40 ml / min in 0.1% TFA (aq) over 6.0 min) Was isolated (50 mg, 23%, MS: m / e = 292.1 [M + H ⁺ ]).

Example 3

(5-Chloro-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine

Similar to Example 1, the title compound was prepared from 2-amino-6-chlorobenzylamine (MS: m / e = 326.3 [M + H ⁺ ]).

Example 4

(3,4-Dihydro-quinazolin-2-yl) -m-tolyl-amine

Similar to Example 2, the title compound was prepared from 2-aminobenzylamine and m-toluidine (MS: m / e = 238.3 [M + H ⁺ ]).

Example 5

(3,4-Dihydro-quinazolin-2-yl) -indan-5-yl-amine

Similar to Example 2, the title compound was prepared from 2-aminobenzylamine and 5-aminoindane (MS: m / e = 264.4 [M + H ⁺ ]).

Example 6

(3,4-Dihydro-quinazolin-2-yl) -naphthalen-1-yl-amine

Similar to Example 2, the title compound was prepared from 2-aminobenzylamine and 1-naphthylamine (MS: m / e = 274.2 [M + H ⁺ ]).

Example 7

(3-Bromo-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine

Similar to Example 2, the title compound was prepared from 2-aminobenzylamine and 3-bromoaniline (MS: m / e = 302.1 [M + H ⁺ ]).

Example 8

(5,6-Dichloro-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine

Similar to Example 1, the title compound was prepared from 2-amino-5,6-dichlorobenzylamine (MS: m / e = 360.0 [M + H ⁺ ]).

Example 9

(4-chloro-3-trifluoromethyl-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine; Hydriyoidide

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 4-chloro-3- (trifluoromethyl) phenyl isothiocyanate (MS: m / e = 326.3 [M + H ⁺ ] ). Instead of HPLC purification of step c), the final product was isolated by filtration from the reaction mixture.

Example 10

(3-Chloro-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine

Similar to Example 2, the title compound was prepared from 2-aminobenzylamine and 3-chloroaniline (MS: m / e = 258.0 [M + H ⁺ ]).

Example 11

(3,5-bis-trifluoromethyl-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 3,5-trifluorophenylisothiocyanate (MS: m / e = 360.2 [M + H ⁺ ]).

Example 12

(3,4-Dihydro-quinazolin-2-yl)-(3-methoxy-phenyl) -amine

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 3-methoxyphenylisothiocyanate (MS: m / e = 254.1 [M + H ⁺ ]).

Example 13

(3,4-dihydro-quinazolin-2-yl)-(3-fluoro-phenyl) -amine; Hydriyoidide

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 3-fluorophenylisothiocyanate (MS: m / e = 242.0 [M + H ⁺ ]). Instead of HPLC purification of step c), the final product was isolated by filtration from the reaction mixture.

Example 14

(3,4-dihydro-quinazolin-2-yl)-(4-fluoro-phenyl) -amine; Hydriyoidide

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 4-fluorophenylisothiocyanate (MS: m / e = 242.2 [M + H ⁺ ]). Instead of HPLC purification of step c), the final product was isolated by filtration from the reaction mixture.

Example 15

(4-Chloro-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 4-chlorophenylisothiocyanate (MS: m / e = 257.9 [M + H ⁺ ]).

Example 16

(3,4-dihydro-quinazolin-2-yl)-(2-fluoro-phenyl) -amine; Hydriyoidide

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 2-fluorophenylisothiocyanate (MS: m / e = 242.3 [M + H ⁺ ]). Instead of HPLC purification of step c), the final product was isolated by filtration from the reaction mixture.

Example 17

3- (3,4-dihydro-quinazolin-2-ylamino) -benzonitrile; Hydriyoidide

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 3-cyanophenylisothiocyanate (MS: m / e = 249.1 [M + H ⁺ ]). Instead of HPLC purification of step c), the final product was isolated by filtration from the reaction mixture.

Example 18

(3,4-Dihydro-quinazolin-2-yl) -o-tolyl-amine

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 2-methylphenylisothiocyanate (MS: m / e = 238.3 [M + H ⁺ ]).

Example 19

(2-Chloro-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine

Similar to Example 2, the title compound was prepared from 2-aminobenzylamine and 2-chloroaniline (MS: m / e = 258.0 [M + H ⁺ ]).

Example 20

(3,4-Dihydro-quinazolin-2-yl) -p-tolyl-amine

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 4-methylphenylisothiocyanate (MS: m / e = 238.3 [M + H ⁺ ]).

Example 21

4- (3,4-Dihydro-quinazolin-2-ylamino) -benzonitrile

Similar to Example 1, the title compound was prepared from 2-aminobenzylamine and 4-cyanophenylisothiocyanate (MS: m / e = 249.0 [M + H ⁺ ]).

Example 22

(3,4-Dihydro-quinazolin-2-yl)-(2-methoxy-phenyl) -amine

Similar to Example 2, the title compound was prepared from 2-aminobenzylamine and o-anisidine (MS: m / e = 254.2 [M + H ⁺ ]).

Example 23

(3,4-dihydro-quinazolin-2-yl)-(4-methoxy-phenyl) -amine; Hydriyoidide

Similar to Example 2, the title compound was prepared from 2-aminobenzylamine and p-anisidine (MS: m / e = 254.1 [M + H ⁺ ]). Instead of HPLC purification of step c), the final product was isolated by filtration from the reaction mixture.

Claims (13)

Use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of a 5-HT _5A receptor related disease: Formula I

Where R ¹ is hydrogen, lower alkyl or halogen; R ² is hydrogen, lower alkyl, lower alkoxy, halogen, lower alkyl substituted by halogen or cyano; Aryl is phenyl, naphthyl or indan-5-yl; n is 1 or 2. The method of claim 1, Depression, anxiety disorder, schizophrenia, panic disorder, agoraphobia, social fear, obsessive compulsive disorder, post traumatic stress disorder, pain, memory disorder, dementia, eating behavior disorder, sexual dysfunction, sleep disorder, withdrawal due to substance abuse, Use of a compound of formula (I) for the treatment of motility disorders such as Parkinson's disease, mental disorders or gastrointestinal disorders. The method of claim 2, Use of a compound of formula (I) for the treatment of anxiety, depression, sleep disorders and schizophrenia. The method of claim 1, Use of a compound of formula (I) wherein aryl is phenyl. The method of claim 4, wherein The compound is (5-methyl-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine, (3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine, (5-chloro-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine, (3,4-dihydro-quinazolin-2-yl) -m-tolyl-amine, (3-bromo-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine, (5,6-dichloro-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine, (4-chloro-3-trifluoromethyl-phenyl)-(3,4-dihydro-quinazolin-2-yl)-amine, (3-chloro-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine, (3,5-bis-trifluoromethyl-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine, (3,4-dihydro-quinazolin-2-yl)-(3-methoxy-phenyl) -amine or (3,4-Dihydro-quinazolin-2-yl)-(3-fluoro-phenyl) -amine Uses. The method of claim 1, Use of a compound of formula (I) wherein aryl is indan-5-yl. The method of claim 6, The compound is (3,4-dihydro-quinazolin-2-yl) -indan-5-yl-amine. The method of claim 1, Use of a compound of formula I wherein aryl is naphthyl. The method of claim 8, The compound is (3,4-dihydro-quinazolin-2-yl) -naphthalen-1-yl-amine. A process for preparing a compound of formula (I) as defined in claim 1, a) reacting a compound of formula II with MeI to obtain a compound of formula I; or b) reacting a compound of formula III with a compound of formula IV to yield a compound of formula I; And c) if necessary, converting the obtained compound to a pharmaceutically acceptable acid addition salt: Formula II

Formula III

Formula IV

Formula I

Where R ¹ , R ² , aryl and n are as defined in claim 1. Depression, anxiety disorder, schizophrenia, panic disorder, agoraphobia, social fear, obsessive compulsive disorder, post traumatic stress disorder, pain, memory disorder, dementia, eating behavior disorder, sexual dysfunction, sleep disorder, withdrawal due to substance abuse, A medicament containing at least one compound of formula (I) according to claim 1 and a pharmaceutically acceptable excipient for the treatment of motility disorders such as Parkinson's disease, mental disorders or gastrointestinal disorders. The method of claim 11, The compound is (5-methyl-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine, (3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine, (5-chloro-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine, (3,4-dihydro-quinazolin-2-yl) -m-tolyl-amine, (3-bromo-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine, (5,6-Dichloro-3,4-dihydro-quinazolin-2-yl)-(3-trifluoromethyl-phenyl) -amine, (4-chloro-3-trifluoromethyl-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine, (3-chloro-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine, (3,5-bis-trifluoromethyl-phenyl)-(3,4-dihydro-quinazolin-2-yl) -amine, (3,4-dihydro-quinazolin-2-yl)-(3-methoxy-phenyl) -amine, (3,4-dihydro-quinazolin-2-yl)-(3-fluoro-phenyl) -amine, (3,4-dihydro-quinazolin-2-yl) -indan-5-yl-amine or (3,4-Dihydro-quinazolin-2-yl) -naphthalen-1-yl-amine Phosphorus. Invention as described above.